Nature Communications (Jan 2025)
Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma
- Soniya Bastola,
- Marat S. Pavlyukov,
- Neel Sharma,
- Yasmin Ghochani,
- Mayu A. Nakano,
- Sree Deepthi Muthukrishnan,
- Sang Yul Yu,
- Min Soo Kim,
- Alireza Sohrabi,
- Natalia P. Biscola,
- Daisuke Yamashita,
- Ksenia S. Anufrieva,
- Tatyana F. Kovalenko,
- Grace Jung,
- Tomas Ganz,
- Beatrice O’Brien,
- Riki Kawaguchi,
- Yue Qin,
- Stephanie K. Seidlits,
- Alma L. Burlingame,
- Juan A. Oses-Prieto,
- Leif A. Havton,
- Steven A. Goldman,
- Anita B. Hjelmeland,
- Ichiro Nakano,
- Harley I. Kornblum
Affiliations
- Soniya Bastola
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
- Marat S. Pavlyukov
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
- Neel Sharma
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
- Yasmin Ghochani
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
- Mayu A. Nakano
- Precision Medicine Institute, University of Alabama at Birmingham
- Sree Deepthi Muthukrishnan
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
- Sang Yul Yu
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
- Min Soo Kim
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
- Alireza Sohrabi
- Department of Bioengineering, University of Texas at Austin
- Natalia P. Biscola
- Department of Neurology, Icahn School of Medicine at Mount Sinai
- Daisuke Yamashita
- Department of Neurosurgery, Ehime University Graduate School of Medicine, Shitsukawa 454
- Ksenia S. Anufrieva
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine of Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency
- Tatyana F. Kovalenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry
- Grace Jung
- Department of Medicine, Center for Iron Disorders, David Geffen School of Medicine at UCLA
- Tomas Ganz
- Department of Medicine, Center for Iron Disorders, David Geffen School of Medicine at UCLA
- Beatrice O’Brien
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
- Riki Kawaguchi
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
- Yue Qin
- Interdepartmental Program in Bioinformatics, Program in Neurogenetics, Department of Neurology and Department of Human Genetics, David Geffen School of Medicine at UCLA
- Stephanie K. Seidlits
- Department of Bioengineering, University of Texas at Austin
- Alma L. Burlingame
- Department of Pharmaceutical Chemistry, University of California
- Juan A. Oses-Prieto
- Department of Pharmaceutical Chemistry, University of California
- Leif A. Havton
- Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, James J Peters VA Medical Center
- Steven A. Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center
- Anita B. Hjelmeland
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham
- Ichiro Nakano
- Department of Neurosurgery, Harada Hospital, Iruma
- Harley I. Kornblum
- The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
- DOI
- https://doi.org/10.1038/s41467-024-55487-1
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 1 – 20
Abstract
Abstract Extensive neovascularization is a hallmark of glioblastoma (GBM). In addition to supplying oxygen and nutrients, vascular endothelial cells provide trophic support to GBM cells via paracrine signaling. Here we report that Endocan (ESM1), an endothelial-secreted proteoglycan, confers enhanced proliferative, migratory, and angiogenic properties to GBM cells and regulates their spatial identity. Mechanistically, Endocan exerts at least part of its functions via direct binding and activation of the PDGFRA receptor. Subsequent downstream signaling enhances chromatin accessibility of the Myc promoter and upregulates Myc expression inducing stable phenotypic changes in GBM cells. Furthermore, Endocan confers radioprotection on GBM cells in vitro and in vivo. Inhibition of Endocan-PDGFRA signaling with ponatinib increases survival in the Esm1 wild-type but not in the Esm1 knock-out mouse GBM model. Our findings identify Endocan and its downstream signaling axis as a potential target to subdue GBM recurrence and highlight the importance of vascular-tumor interactions for GBM development.
